The use of adoptive transfer therapy in combination with chemotherapy to treat neoplastic disease forms the basis for adoptive chemo-immunotherapy. In murine models, adoptive transfer of T cells in conjunction with administration of some chemotherapeutic agents has successfully treated significant numbers of tumor-bearing hosts [P. Greenberg et al, J. Exp. Med., 161:1122-1134 (1985); M. Bookman et al, J. Immunol., 139:3166-3170 (1987); and F. Fornelle et al, Int. J. Cancer, 42:952-957 (1988)]. Results from the few clinical trials conducted so far have demonstrated that TIL/IL-2 therapy together with adriamycin, mitomycin or cyclophosphamide treatment represents a promising therapeutic approach in patients with metastatic or primary liver tumors and melanoma [A. Kawata et al, Am. J. Clin. Oncol., 18:257-262 (1995); S. Rosenberg et al, N. Engl. J. Med., 319:1676-1680 (1988); and J. Gold et al, Eur. J. Cancer, 31A:698-708 (1995)]. The mechanisms underlying the improved antitumor effects obtained with the combined regimens have not been fully elucidated. However, the immunomodulatory activity displayed by some chemotherapeutic agents seems to play a critical role in determining the superiority of chemo-immunotherapy versus single agent treatment [M. Awwad et al, Immunology, 65:87-92 (1988) and R. North, J. Exp. Med., 155:1063-1074 (1982)]. Despite these clinical results, the toxicity involved with LAK or TIL/IL-2 therapy [K. Margolin et al, J. Clin. Oncol., 7:486 (1989)] and the scarcity of tumor specimen for preparation and expansion of TIL [S. Topalian et al, J. Immunol. Meth., 102:127-141 (1987)] are important limiting factors for the use of cell therapy in conjunction with other approaches.
A new adoptive transfer strategy to cancer that might overcome the limitations of LAK and TIL therapy because it does not require the concomitant administration of exogenous, toxic cytokines, such as IL-2, for efficacy have been developed. This approach is based on the use of a lethally irradiated human T cell line (TALL-104), (CD3/TCR.alpha..beta..sup.+ CD8.sup.+ CD16.sup.-) [A. Cesano et al, In Vitro Cell. Dev. Biol., 28A:648 (1992); A. Cesano et al, J. Immunol., 151:2943-2957 (1993); and A. Cesano et al, Cancer Immunol. Immunoth., 40:139 (1995)], which is endowed with MHC non-restricted killer activity against a broad range of tumors across several species, while sparing cells from normal tissues. Studies in immunodeficient and immunocompetent murine models with transplantable tumors and in canines with spontaneously arising cancers, suggest the potential of this cell line as an anti-tumor agent in a clinical setting [A. Cesano et al, J. Clin. Invest., 94:1076 (1994); A. Cesano et al, Cancer Res., 55:96 (1995); A. Cesano et al, Cancer Res., 56:3021 (1996); and A. Cesano et al, Cancer Res., 56:4444-4452 (1996)].
However, despite the progress made in recent years in the management of various forms of hematological and non-hematological malignancies (i.e., solid tumors), it has become clear that single therapeutic approaches, such as surgery, chemotherapy, radiation therapy, and biological therapies are often not effective in eradicating or drastically reducing tumor burden. Optimal therapy for refractory tumors requires multiple combination approaches.
What are needed are methods of treating cancers which are resistant to single forms of treatment, and particularly, which are resistant to chemotherapy. In addition, methods of reducing the toxicity of otherwise effective anti-cancer chemotherapeutic regimens are needed.